In addition to the array of guest actors portraying the patients of the interns, several actors appear across the season in multi-episode arcs. Kate Burton appears as Meredith's mother, Ellis Grey, a famed surgeon who now suffers from Alzheimers. Sarah Utterback also appears as Olivia Harper, a nurse at Seattle Grace who forms a relationship with George but is revealed to have past connections to Alex. Future main cast remember Kate Walsh makes one guest appearance as Addison Montgomery-Shepherd in the season finale, signalling the start of her two year run in the series.

Plot: Meredith Grey is in a program at Seattle Grace Hospital where she will spend the next seven years. In the program, Meredith finds out Derek is her new doctor while her interns Cristina, George and Izzie struggle with the rigours under the tutilage of Miranda.

Recurring characters: Kate Burton as Ellis Grey

The First Cut Is The Deepest
Episode number: 02

Original air date: April 2, 2005

Plot: The surgical staff tries to be optimistic as a young woman clings to life after a brutal attack. Meredith save a newborn in the hospital nursery; while taking on the responsibility of an object that she wished she never had to look after and George, Alex, Cristinaand Izzie learn that it takes more than to be good at their jobs.

Recurring characters: None

Winning A Battle, Losing The War
Episode number: 03

Original air date: April 10, 2005

Plot: When a bike race leaves one pedestrian brain dead, interns Cristina and Izzie face an emotional crisis of conscience: how long does one wait before they start harvesting his organs? Cristina is all detached professionalism, but ever-hopeful Izzie prays for a miracle. Meanwhile, Georgeavoids a flirtatious patient while Meredith copes with living with roommates and tries to dodge Derek's ever-increasing advances.

Recurring characters: None

No Man's Land
Episode number: 04

Original air date: April 17, 2005

Plot: When a retired nurse at Seattle Grace is admitted, Cristina takes on her case and is forced to confront her competitive spirit. A patient who recognizes Izzie from a modeling photo does not want her to treat him while Alex humiliates Izzie in front of everyone. Meredith and Derek treat a construction worker who surprisingly survived his injuries, but have bad news for his wife about his future and George feels emasculated by his roommates.

Recurring characters: Kate Burton as Ellis Grey

Shake Your Groove Thing
Episode number: 05

Original air date: April 24, 2005

Plot: Meredith realizes that she must take on a lot more responsibility in her personal life when she is told that her mother needs to sign over all of her assets to her, and in her professional life when she fears she made a grave mistake during her first heart surgery. Izzie's commitment to her job is questioned when her boyfriend makes a visit to Seattle and Cristinabonds with Burke.

Recurring characters: Kate Burton as Ellis Grey

If Tomorrow Never Comes
Episode number: 06

Original air date: May 1, 2005

Plot: All of the interns are in awe when a woman comes in with a record breaking tumor and when Alex seems to show her genuine compassion. Now that Baileyknows about Meredith and Derek's affair, their jobs are in jeopardy, and she advises Meredith to end it. Meanwhile, Cristina and Burke's secret relationship is also getting more complicated and Izzie tries to get George to find the courage to ask Meredith out.

Recurring characters: None

The Self-Destruct Button
Episode number: 07
Original air date: May 1, 2005
Plot: Derek and Meredith try to spend the night together, but their haggard appearance speaks volumes to everyone including Bailey, who warns Meredith to end the relationship and Izzie who lashes out at Meredith. Meanwhile, George suspects an anesthesiologist if drinking on the job and Cristina's battles the flu while trying to not let it affect her surgical skills.
Recurring characters:Sarah Utterback as Olivia Harper

Save Me
Episode number: 08

Original air date: May 15, 2005

Plot: Meredith grows increasingly dissatisfied with the unknown details of Derek's life. Meanwhile, Alextreats a patient whose religious beliefs jeopardize her chances for recovery; Izzie contemplates reconnecting with her estranged mother and Cristina's has a unexpected pregnancy.

Recurring characters:Sarah Utterback as Olivia Harper

Who's Zoomin' Who?
Episode number: 07

Original air date: May 22, 2005

Plot: Richard reluctantly tells Derek about his concern about his own health as George's relationship with Olivia is tested when he develops a sexually transmitted disease. Izzie and Cristina worry about a patient's wife and daughter who can't agree on his care while Burke treats his best friend, whose medical diagnosis raises some questions regarding his wife's actions. Meredith and Derek grow closer.

The first season was originally intended to comprise of 14 episodes, ending with "Bring The Pain". However, the season was reduced to nine episodes so ABC would be able to air the season finale alongside the season finale of fellow freshman drama Desperate Housewives. As a consequence, "Who's Zoomin' Who?" aired as the season finale and the cliffhanger became the arrival of Addison and not Meredith waiting for Derek at the bar at the end of "Bring The Pain" as originally intended. The five episodes produced as season one episodes but not aired where pushed back and aired as the first five season two episodes beginning Septemnber 25, 2005.

As a result of this, some regions aired the season as a fourteen episode run while other showcased nine episodes as the first season.